Osteoporosis can be classified into postmenopausal osteoporosis and senile osteoporosis. Postmenopausal osteoporosis occurs due to an increase in bone resorption caused by activation of an osteoclast arising from a rapid hormonal change caused by menopause. Further, senile osteoporosis occurs due to a decrease in bone formation caused by a decrease in a function of an osteoblast caused by aging. Bone fractures caused by osteoporosis lead to severe restriction on activity. In particular, hip fracture is involved in high mortality of about 15 to 35%. Therefore, it is important to diagnose and treat osteoporosis prior to occurrence of osteoporotic fractures.
Conventionally, bisphosphonate-based medicines have been known as medicines for treating osteoporosis. It is known that bisphosphonate sticks to an inorganic element of bone and when an osteoclast resorbs the bone to which bisphosphonate sticks, a non-hydrolyzed ATP analogue is formed and exhibits toxicity on the cell or causes a decrease in activity of the osteoclast and apoptosis in various ways in the osteoclast, thereby reducing bone resorption and thus increasing a bone density. Although such medicines have been known as being relatively safe, there have been recently suggested that when being used for a long time, the medicines may affect remodeling of bone by normal bone resorption or bone formation, or healing of bone after fracture, resulting in a decrease in bone elasticity and a bad effect on bone strength. There is a report that the medicines actually cause stress fractures in numerous patients.
Accordingly, development of novel bone metabolism involved in occurrence of osteoporosis and development of a medicine for preventing or treating osteoporosis has been desperately needed.
A bone marrow stem cell niche is defined as a molecular microenvironment where cells' functions and fates are regulated by interactions between various cells including a bone marrow stem cell present in bone marrow. So far, there have been known roughly two kinds of bone marrow stem cell niches including “endosteal niche” and “perivascular niche”.
Firstly, “endosteal niche” refers to a microenvironment where basal cells are present in bone marrow, and basal cells, osteoblasts, and osteoclasts are mainly present. In the endosteal niche, these cells are adjacent to other cells, particularly hematopoietic progenitor cells (HPCs) or hematopoietic stem cells (HSCs) by intracellular adhesion factors (CXCL12, Ang-1, VCAM1, stem cell factor, IL-7, and the like), and the hematopoietic stem cells sticking to the osteoblasts are mobilized to blood in response to a neurotransmission signal from the outside or homed to the bone marrow so as to affect homeostatic maintenance in the bone marrow.
Further, “perivascular niche” refers to a microenvironment constituted by macrophages, bone marrow mesenchymal stem cells (MSCs), and CAR cells (CXCL12 abundant reticular cells). In the perivascular niche, these cells are adjacent to hematopoietic cells by intracellular adhesion factors and the hematopoietic stem cells sticking to the macrophages and the bone marrow mesenchymal stem cells are mobilized to blood in response to a neurotransmission signal, such as stress or a neurotransmitter, from the outside in a similar manner to the endosteal niche.
As described above, the bone marrow stem cells are mobilized to a bloodstream or homed in the bone marrow niche. Mobilization of bone marrow stem cells to blood is an important phenomenon occurring in bone marrow when the body is stressed or damage, and refers to a phenomenon in which stem cells, immune-related cells, and osteoclasts move from bone marrow to a blood vessel. The cells mobilized to the blood vessel move along a blood stream to a lesion site and help to heal the lesion. Meanwhile, the bone marrow stem cells that finish the healing action in the lesion site return to the bone marrow along the blood stream, and such a phenomenon is referred to as “homing”.
A bone marrow hematopoietic stem cell can be differentiated into lymphoid cells and myeloid cells in bone marrow. An osteoclast as one of the myeloid cells differentiated from the bone marrow hematopoietic stem cell maintains bone formation and bone erosion through a balance between the osteoclast and an osteoblast in the bone marrow. If such a balance is broken, there is an increase in the number of osteoclasts and an increase in a speed of bone erosion, resulting in occurrence of osteoporosis.
It is known that if S1P (sphingosine-1-phosphate) as a material for inducing mobilization of osteoclast precursors to blood is administered or an S1P receptor agonist (FTY720) is administered in order to decrease the number of osteoclasts in bone marrow, there is an increase in bone formation. Likewise, if mobilization of bone marrow hematopoietic stem cells as primitive cells for osteoclasts to blood is induced, there is a decrease in differentiation into osteoclasts, and, thus, the number of osteoclasts in bone marrow is decreased.
The inventors of the present disclosure have carefully tried to discover a novel active molecule which can be used for treating osteoporosis. As a result thereof, the inventors of the present disclosure found that a short peptide having a specific sequence induces mobilization of hematopoietic stem cells to blood as described above and causes a decrease in the number of osteoclasts, and, thus, decreases bone erosion caused by osteoclasts, thereby suppressing progress of an osteoporotic lesion, and denominated the peptide as “Osteopep2”.